Potent negative regulation mechanisms, including immunosuppression, mediated by regulatory T cells (Treg cells) in the tumor microenvironment are major obstacles to the treatment of tumors (Non Patent Literature 1).
For example, CD4-positive Treg cells which infiltrate tumors may be able to strongly inhibit antitumor immune response and may become a major obstacle to effective cancer treatment.
Tumor immunosuppression mediated by CD4-positive FoxP3-positive Treg cells has been sufficiently demonstrated in animal tumor models. It has been reported that systemic (including intratumoral) Treg cell removal produces an antitumor effect, wherein the removal of approximately 50% tumor-infiltrating Treg cells is not effective (Non Patent Literature 2).
It has been reported that the increased ratio of CD4-positive CD25-positive Treg cells (cell population including Treg cells) to the whole CD4-positive T cell population in humans is intratumorally detected in patients with various cancers including lung, breast, and ovary tumors, and the abundance ratio correlates negatively with the survival probabilities of the patients (Non Patent Literatures 3 to 8).
The removal of CD4-positive CD25-positive Treg cells from tumors using an anti-CD25 antibody has been confirmed to produce an antitumor effect. However, this removal is not specific for the Treg cells because CD25 is expressed on the cell surface of the CD4-positive CD25-positive Treg cells as well as newly activated effector T cells. Furthermore, the administration of an anti-CD25 antibody to mice brings about a limited antitumor effect. It has been demonstrated in various tumor models that only the antibody administration before tumor inoculation exhibits a therapeutic effect, whereas the administration of the antibody after tumor engraftment in mice rarely produces a therapeutic effect. The antitumor effect was attenuated in the case of starting the administration of an anti-CD25 antibody at post-transplant day 1, and was rarely observed in the case of starting the administration of an anti-CD25 antibody at post-transplant day 2 or later (Non Patent Literature 9).
Drug efficacy tests have been carried out so far by administering antibodies to mice for the purpose of removing Treg cells. Nonetheless, there are few reports showing an antitumor effect. Thus, it is very difficult to confirm an antitumor therapeutic effect brought about by Treg cell removal by antibody administration before inoculation (Non Patent Literature 10).
CCR8, also previously called CY6, CKR-L1 or TER1, is a G protein-coupled 7-transmembrane CC chemokine receptor protein expressed in the thymus, the spleen, etc. A gene encoding this protein resides on human chromosome 3p21. Human CCR8 consists of 355 amino acids (Non Patent Literature 11). CCL1 is known as an endogenous ligand for CCR8 (Non Patent Literature 12). Human CCR8 cDNA is constituted by the nucleotide sequence represented by GenBank ACC No. M_005201.3, and mouse CCR8 cDNA is constituted by the nucleotide sequence represented by GenBank ACC No. NM_007720.2.